N,N&#34;(pyridinediyl)dioxamate compounds

ABSTRACT

It has now been discovered, that compounds of FIG.

BRIEF SUMMARY OF THE INVENTION

It has now been discovered that novel compounds of FIG. 1 are useful inthe prophylactic treatment of sensitized humans and animals for allergyand all anaphylactic reactions of a reagin or non-reagin mediatednature. Additionally, the compounds are intermediates to thebiologically active dioxamic acids and their salts. The compounds areformulated with pharmaceutical carriers for oral, parenteral, inhalationor rectal means of administration.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, there are provided compoundsrepresented by FIG. 1, and hereafter referred to as Group A, ##SPC2##

and N-oxides thereof wherein each ##EQU1## group is located anywhere onthe carbon ring with the proviso that one group cannot be ortho to theother group;

X and Y can be the same or different and are selected from the groupconsisting of hydrogen, alkyl from one through four carbon atoms,phenyl, alkoxy from one through four carbon atoms, nitro, amino,trifluoromethyl, halogen, cyano and ##EQU2## wherein D is selected fromthe group consisting of hydrogen, alkyl from 1 through 6 carbon atomsand a physiologically acceptable metal or amine cation.

R₁ and R₂ are the same or different and are selected from the groupconsisting of hydrogen; a physiologically acceptable metal or aminecation; alkyl of 7 to 12 carbon atoms, inclusive; cycloalkyl of four toeight carbon atoms, inclusive; ##SPC3##

Wherein p is an integer of zero to four, inclusive, and S is selectedfrom the group consisting of hydrogen, alkyl of one to six carbon atoms,inclusive, phenyl, halogen, trigluoromethyl, hydroxy, alkoxy of 1 to 4carbon atoms, inclusive, amino, nitro, carboxy, cyano, and ##EQU3##wherein R₃ and R₄ are the same or different and are selected from thegroup consisting of hydrogen and alkyl of one to four carbon atoms,inclusive; with the proviso that when p is zero, S is not hydrogen; and##EQU4## wherein b is an integer of 2 to 4, inclusive, and R₅ and R₆ arethe same or different and are selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms, inclusive, and when R₅ and R₆are taken together with the nitrogen atom to which they are attachedform a saturated heterocyclic of 3 to 6 ring carbon atoms, inclusive;with the further proviso that when one of R₁ and R₂ is hydrogen or aphysiologically acceptable metal or amine cation, the other variable isnot hydrogen or a physiologically acceptable metal or amine cation; andphysiologically acceptable acid addition salts thereof.

Another group of compounds, hereafter referred to as Group B, arecompounds where X and Y are the same or different and are selected fromthe group consisting of hydrogen, alkyl of one to four carbon atoms,inclusive, phenyl, alkoxy of one to four carbon atoms, inclusive, nitro,trifluoromethyl, halogen, cyano and ##EQU5## the location of the##EQU6## groups and R₁ and R₂ are identified as in Group A.

A further group of compounds, hereafter referred to as Group C, arecompounds wherein the ##EQU7## groups are located at the 2 and 6positions or the 3 and 5 positions. X and Y and R₁ and R₂ are defined asin Group B.

A still further group of compounds, hereafter referred to as Group D,are compounds wherein the location of the ##EQU8## groups are defined asin Group C, X is hydrogen, Y is selected from the group consisting ofhydrogen, alkyl of one to four carbon atoms, inclusive, alkoxy of 1 to 4carbon atoms, inclusive, nitro, trifluoromethyl, halogen, cyano, and##EQU9## R₁ and R₂ are the same or different and are selected from thegroup consisting of alkyl of seven to ten carbon atoms, inclusive;cycloalkyl of four to seven carbon atoms, inclusive; and ##SPC4##

wherein p is an integer of 0 to 4, inclusive, and S is selected from thegroup consisting of hydrogen, alkyl of 1 to 4 carbon atoms, inclusive,alkoxy of 1 to 4 carbon atoms, inclusive, halogen, carboxy, and cyano,with the proviso that when p is zero, S is not hydrogen.

A further group of compounds, hereafter referred to as Group E, arecompounds wherein X, R₁, R₂ and the location of the ##EQU10## groups aredefined as in Group D. Y is at position 4 and is defined as in Group D.

A still further group of compounds, hereafter referred to as Group F,are compounds wherein R₁, R₂, X and Y are as defined in Group E and thelocation of the ##EQU11## groups are at the 2 and 6 positions.

A further group of compounds, hereafter referred to as Group G, arecompounds wherein the location of the ##EQU12## groups, X and Y aredefined as in Group F, with the proviso that halogen is fluoro, chloro,and bromo. R₁ and R₂ are the same or different and are selected from thegroup consisting of alkyl of seven to ten carbon atoms, inclusive, and##SPC5##

wherein p is 1 or 2 and S is selected from the group consisting ofhydrogen, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4carbon atoms, inclusive, fluoro, chloro, bromo, cyano, and carboxy.

A still further group of compounds are compounds of successive Groups D,E, F and G with the proviso that the N-oxide is excluded and R₁ and R₂are defined as in Group G.

Preferred R₁ and R₂ groups are the above scopings when R₁ is the same asR₂. It should be noted that when R₁ and R₂ are the same, neither R₁ norR₂ can be hydrogen or a physiologically acceptable metal or aminecation.

Most preferred groups are the dibenzyl and diphenylethyl dioxamates.

As employed in the above disclosure and throughout the specification,the term "halogen" includes fluoro, chloro, bromo, and iodo. The phrase"alkyl of 1 to 6 carbon atoms, inclusive," includes methyl, ethyl,propyl, butyl, pentyl, hexyl and isomers thereof. Illustrative examplesof isomers are isopropyl, tert. butyl, neopentyl, and 2,3-dimethylbutyl.When alkyl is limited to a lesser number of carbon atoms, the samescoping is intended within that number of carbon atoms. The phrase"alkyl of 2 to 12 carbon atoms, inclusive" includes heptyl, octyl,nonyl, decyl, undecyl, dodecyl and isomers thereof. Illustrativeexamples of isomers are isoheptyl, 2,2,4-trimethyloctyl,2-propyl-4-methylpentyl, isodecyl, tert. undecyl and isododecyl.

The phrase "a physiologically acceptable metal or amine cation" is thatmetal or amine which is accepted in an essentially non-toxic manner by amammal. Illustrative examples of such metals are the alkali metals,e.g., lithium, sodium and potassium, and the alkaline earth metal, e.g.,magnesium and calcium. Other metals, e.g., aluminum, zinc and iron arealso within the scope of this invention. Illustrative of the amines arethose derived from primary, secondary, or tertiary amines. Examples ofsuitable amines are methylamine, dimethylamine, triethylamine,ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine,decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine,dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine,β-phenylethylamine, ethylenediamine, diethylenetriamine, and likealiphatic, cycloaliphatic, and araliphatic amines containing up to andincluding about eighteen carbon atoms, as well as heterocyclic amines,e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkylderivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, glactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,procaine, and the like. Also included within the amine scope arequaternary amines such as ammonium, tetramethylammonium,tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, andthe like.

Physiologically acceptable acid addition salts refer to the salts whichcan be prepared at the nitrogen of the pyridine ring. Illustrative ofthese salts are hydrochloric, hydrobromic, hydriodic, nitric, sulfuric,oxalic, cyclohexanesulfamic, salicyclic, and the like.

The compounds of the invention can be prepared by methods known in theart. For example, methods outlined in U.S. Pat. No. 3,639,249, Column 3,line 38, to Column 5, line 18, can be used with facility. Theappropriately substituted diaminopyridines are suitable startingmaterials. These compounds are reacted with an R₁ substituted oxalylhalide, R₁ not being a physiologically acceptable metal or amine cationin a suitable solvent and base to form a dioxamate of FIG. 1. The estercan then be transesterified with known reagents and conditions to form adifferent ester. If less than stoichiometric quantities are employed inthe transesterification, esters where R₁ and R₂ differ are readilyprepared. After formation of the ester, less than stiochiometricquantities of reagents can be employed to prepare the half metal, halfacid, or half amine salt -- the other half of the molecule being theester moiety.

As stated previously, the appropriate substituted diamino pyridine isreacted with an R₁ oxalyl halide, for example, butyloxalylchloride toform the dioxamate. The reaction is carried out in base and solvent atthe standard conditions, as exemplified by the art. Examples of suitablesolvents are dimethylformamide, dioxane, and tetrahydrofuran.Appropriate bases include triethylamine, N-methylmorpholine,dimethylpiperazine and N-methylpiperidine.

Alternatively, A diR₁ oxalate is employed. The appropriately substituteddiamino pyridine is heated together with the oxalate or an additionalsolvent such as a xylene or diphenyl ether if desired, thereby formingthe dioxamate. The temperature is from about 25°C. to the refluxtemperature of the system, preferably temperature between about 100°C.and the reflux temperature.

The N-oxide derivative of the pyridyl dioxamate can be readily preparedby oxidation of the diester with an oxidizing agent, such asm-chloroperoxy benzoic acid.

The appropriately X and Y substituted diaminopyridine starting materialsare prepared by conventional substitution means well known in the art.These means depend somewhat upon the substituent itself, the placementof the substituent and the placement of the oxamic group.

The particular ##EQU13## substituents can be prepared by converting thecorresponding diamino or dinitro pyridinecarboxylic acid, for example,to the ester, amide, etc., by standard methods. This can be done priorto the preparation of the dioxamate from the substituted diaminostarting material.

An additional route of preparing the starting materials, (II), forexample, is by reacting a substituted dihalopyridine, for example,dichloropyridine (V) with ammonia under pressure and elevatedtemperature to produce the substituted diaminopyridine starting material(II) ##SPC6##

Illustrative examples of starting materials of FIG. 11 are below.##SPC7##

                                      TABLE 1                                     __________________________________________________________________________    2,6-diamino 2,4-diamino                                                                             2,5-diamino                                                                             3,5-diamino                                   X      Y    X    Y    X    Y    X    Y                                        __________________________________________________________________________    4-BuO  H    3-NO.sub.2                                                                         H    3-CO.sub.2 H                                                                       H    2-OBu                                                                              H                                        4-EtO  H    5-NO.sub.2                                                                         H    3-Cl H    2-Cl H                                        4-MeO  H    3-NO.sub.2                                                                         6-C.sub.3 H.sub.7                                                                  3-C.sub.6 H.sub.5                                                                  H    2-OEt                                                                              H                                        3-NO.sub.2                                                                           H    6-Br H    3-CN H    2-OMe                                                                              H                                        3-NO   H    6-Br 3-CN 3-CF.sub.3                                                                         H    2-O-Pr                                                                             H                                        4-Cl   H    6-Cl 3-CN 3-CH.sub.3                                                                         H    4-C.sub.6 H.sub.5                                                                  H                                        3-l    5-l  6-F  3-CN 3-nBu                                                                              H    4-CN H                                                    6-Et 3-CN 3-Et H    4-CF.sub.3                                                                         H                                        4-Et   H    6-C.sub.6 H.sub.5                                                                  H    3-Pr H    4-CH.sub.3                                                                         H                                        4-i-pentyl-                                                                          H    6-CN H    3-NO.sub.2                                                                         H    4-nBu                                                                              H                                        oxy                                                                           4-CO.sub.2 H                                                                         H    6-CF.sub.3                                                                         H    4-CN H    4-Et H                                        3-CO.sub.2 H                                                                         5-CO.sub.2 H                                                                       6-CH.sub.3                                                                         H    4-CF.sub.3                                                                         H    4-Pr H                                        4-i-OC.sub.3 H.sub.7                                                                 H    6-nBu                                                                              H    4-NO.sub.2                                                                         H    4-NO.sub.2                                                                         H                                                    6-Et H    6-CN H    4-CN 2-Cl                                     4-n-pentyl-                                                                          H    6-Pr H    6-CF.sub.3                                                                         H    4-Et 2-Cl                                     oxy                                                                           3-phenyl                                                                             H    6-NO.sub.2                                                                         H    6-NO.sub.2                                                                         H    4-CF.sub.3                                                                         2-Et                                     3-Br   H    6-CN 3-Cl 3-CN 6-H  4-Pr 2-Br                                     3-MeO  H    6-CF.sub.3                                                                         3-Et 6-Cl 3-CN 4-NO.sub.2                                                                         2-OMe                                    4-Br   H    6-Pr 3-Br 3-CF.sub.3                                                                         6-Cl 4-Cl 2-Et                                     3-OEt  5-OEt                                                                              6-NO.sub.2                                                                         3-OMe                                                                              3-Cl 6-CF.sub.3                                                                         4-Et 2-CF.sub.3                               3-CN   5-CN 6-CH.sub.3                                                                         5-Cl 3-OMe                                                                              6-Et 4-Br 2-Pr                                     4-C.sub.6 H.sub.5                                                                    H    6-OEt                                                                              5-CF.sub.3                                                                         3-COOH                                                                             6-Br 4-OMe                                                                              2-NO.sub.2                               4-CN   H    5-Cl 3-CN 3-iPr                                                                              4-iPr                                                                              2-OMe                                                                              6-OMe                                    4-CF.sub.3                                                                           H    5-CN 3-Cl 3-CN 4-CN 2-CH.sub.3                                                                         6-OEt                                    4-CH.sub.3                                                                           H    5-Cl 3-COOH                                                                             3-Et 4-Cl 2-Cl 6-Cl                                     4-nBu  H    5-COOH                                                                             3-Cl 3-Cl 4-Et 2-CF.sub.3                                                                         6-Cl                                     4-Et   H    5-Me 3-CF.sub.3                                                                         3-OEt                                                                              4-COOH                                                                             2-CN 6-Cl                                     4-iPr  H    5-OEt                                                                              3-NO.sub.2     2-OPr                                                                              6-COOH                                   4-NO.sub.2                                                                           H    5-Et 3-iOPr         2-COOH                                                                             6-COOH                                   4-CN   3-Cl                                                                   4-CF.sub.3                                                                           3-Et                                                                   4-Pr   3-Br                                                                   4-NO.sub.2                                                                           3-OMe                                                                  3-CH.sub.3                                                                           5-Cl                                                                   3-OEt  5-CF.sub.3                                                             4-Cl   3-CN                                                                   4-CN   3-Cl                                                                   4-Cl   3-COOH                                                                 3-COOH 4-Cl                                                                   4-Me   3-CF.sub.3                                                             4-OEt  3-NO.sub.2                                                             4-Et   3-iOPr                                                                 __________________________________________________________________________

TABLE II

Each of the starting materials of TABLE I are converted to a dioxamateof FIG. 1 where R₁ and R₂ are the same and are illustrativelyexemplified by the following:

R₁ = R₂

C₇ h₁₅

i-C₈ H₁₇

2,4-diethylpentyl

i-decyl

dodecyl

cyclobutyl

cyclopentyl

cyclohexyl

cycloheptyl

cyclooctyl

phenyl

benzyl

phenethyl

α,α-dimethylbenzyl

4-(phenyl)butyl

α,α-dimethylphenethyl

p-chlorophenyl

o-isopropylbenzyl

m-pentylphenethyl

3-(p-isohexylphenyl)propyl

m-methoxyphenethyl

p-butoxyphenyl

m-phenylbenzyl

3-(o-fluorophenyl)propyl

m-bromophenethyl

p-(trifluoromethyl)phenyl

m-hydroxyphenethyl

o-aminobenzyl

m-nitrophenyl

p-carboxyphenethyl

m-cyano-α,α-dimethylbenzyl

4-(o-cyanophenyl)butyl

o-(methylamino)phenyl

m-(diethylamino) benzyl

p-(dibutylamino)phenethyl

o-(ethylmethylamino)α,α-dimethylbenzyl

4-[m-(propylamino)phenyl]butyl

2-aminoethyl

3-(methylamino)propyl

4-(ethylamino)butyl

2-(methylpropylamino)ethyl

1-(butylethylamino)-1-methyl

2-(1-azetidinyl)ethyl

3-(1-pyrrolidinyl)propyl

4-(hexahydro-1H-azepin-1-yl)butyl

4-(o-isopropoxyphenyl)butyl

TABLE III

The compounds of Table II are converted to unsymmetrical esters (R₁ ≠R₂) by standard means.

TABLE IV

The compounds of Tables II and III are converted by standard means tohalf esters where either R₁ or R₂ is hydrogen or a physiologicallyacceptable metal or amine cation.

The following example is a compound in accordance with this invention.The compound is not intended to limit but merely to exemplify theinvention.

EXAMPLE 1 Dibenzyl N,N'-(2,6-pyridinediyl)dioxamate

2,6-Diaminopyridine (10.9 g. 0.10 mole) is dissolved in 150 ml. ofanhydrous dimethylformamide containing triethylamine (22.0 g. 0.22mole). The stirred reaction mixture is cooled in an ice bath and benzyloxalyl chloride (41.6 g. 0.21 mole) is added dropwise. The reactionmixture is stirred at room temperature for eighteen hours. The reactionmixture is poured into ice-water (1 l.). The resulting solid product iscollected by filtration, washed with water, and dried at 60° in vacuo.Benzyl oxalyl chloride is prepared in the manner of Number 3234, of thesame invention entity as of this case and filed on the same day. TheSer. No. is 477,816.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, eye drops, oral solutions or suspensions, andoil-in-water and water-in-oil emulsions containing suitable quantitiesof the compound of FIG. I. The preferred method of administration is byinhalation into the lung by means of an aerosol liquid or powder forinsufflation.

For oral administration, either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof FIG. I is mixed with conventional ingredients such as talc, magnesiumstearate, dicalcium phosphate, magnesium aluminum silicate, calciumsulfate, starch, lactose, acacia, methylcellulose, and functionallysimilar materials as pharmaceutical diluents or carriers. Capsules areprepared by mixing the compound with an inert pharmaceutical diluent andfilling the mixture into a hard gelatin capsule of appropriate size.Soft gelatin capsules are prepared by machine encapsulation of a slurryof the compound with an acceptable vegetable oil, light liquidpetrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hyroalcoholic (ethanol) vehicle with suitable sweeteners such as sugarand saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionscan be prepared in substantially the same manner except that thecompound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

Additionally, a rectal suppository can be employed to deliver the activecompound. This dosage form is of particular interest where the mammalcannot be treated conveniently by means of other dosage forms, such asorally or by insufflation, as in the case of young children ordebilitated persons. The active compound can be incorporated into any ofthe known suppository bases by methods known in the art. Examples ofsuch bases include cocoa butter, polyethylene glycols (Carbowaxes),polyethylene sorbitan monostearate, and mixtures of these with othercompatible materials to modify the melting point or dissolution rate.These rectal suppositories can weigh from about 1 to 2.5 Gm.

The preferred compositions are those adapted for inhalation into thelung. For treatment of allergic conditions of the nose, such asrhinitis, compositions adapted for contact with nasal linings arepreferred.

Compositions for inhalation are of three basic types: (1) a powdermixture preferably micropulverized with particle size, preferably fromabout 1 to about 5 microns; (2) an aqueous solution or suspension to besprayed with a nebulizer; and (3) an aerosol with volatile propellant ina pressurized container.

The powders are quite simply prepared by mixing a compound of theformula with a solid base which is compatible with lung tissue,preferably lactose. The powders are packaged in a device adapted to emita measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the FormulaI in water and adding salt to provide an isotonic solution and bufferingto a pH compatible with inhalation. The solutions are dispersed in aspray device or nebulizer and sprayed into the mouth while inhaling.

Aerosols are prepared by dispersing a compound of the FIG. I in water orethanol and mixing with a volatile propellant and placing in apressurized container having a metering valve to release a predeterminedamount of material.

The liquefied propellant employed is one which has a boiling point below65°F. at atmospheric pressure. For use in compositions intended toproduce aerosols for medicinal use, the liquefied propellant should benon-toxic. Among the suitable liquefied propellants which may beemployed are the lower alkanes containing up to five carbon atoms, suchas butane and pentane, or a lower alkyl chloride, such as methyl, ethyl,or propyl, chlorides. Further suitable liquefied propellants are thefluorinated and fluorochlorinated lower alkanes such as are sold underthe trademarks "Freon" and "Genetron". Mixtures of the above-mentionedpropellants may suitably be employed. Examples of these propellants aredichlorodifluoromethane ("Freon 12"), dichlorotetrafluoroethane ("Freon114"), trichloromonofluoromethane ("Freon 11"),dichloromonofluoromethane ("Freon 21"), monochlorodifluoromethane("Freon 22"), trichlorotrifluoroethane ("Freon 113"), difluoroethane("Genetron 142-A") and monochlorotrifluoromethane (Freon 13).

The term "unit dosage form", as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls,dropperfuls, ampuls, vials, aerosols with metered discharges, segregatedmultiples of any of the foregoing, and other forms as herein described.

An effective but non-toxic quantity of the compound is employed intreatment. The dosage of the compound for treatment depends on the routeof administration and the potency of the particular compound. A dosageschedule for humans of from about 0.05 to about 20 mg. of compound in asingle dose, administered parenterally or by inhalation in thecompositions of this invention, are effective for preventing allergyattacks. More specifically, the single dose is from about 0.2 to about20 mg. of compound. The oral and rectal dose is from about 1.0 to about300 mg. in a single dose. More specifically, the single dose is fromabout 10 to about 150 mg. of compound. The dosage to be administered canbe repeated up to four times daily.

The administration of the compositions of the present invention tohumans and animals provides a method for the prophylactic treatment ofallergy or all anaphylactic reactions of a reagin or non-reagin mediatednature. That is to say, these compositions, when administered to asensitized individual prior to the time that the individual comes intocontact with substances (antigens) to which he is allergic, will preventthe allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of suchchronic conditions as bronchial asthma, allergic rhinitis, food allergy,hay fever, urticaria, auto-immune diseases, exercise induced asthma,stress induced asthma, systemic anaphylaxis, and bird fancier's disease.

EXAMPLE 2

A lot of 10,000 tablets, each containing 1 mg. of DibenzylN,N'-(2,6-pyridinediyl)dioxamate is prepared from the following typesand amounts of ingredients:

    ______________________________________                                        Dibenzyl N,N'-(2,6-pyridinediyl)-                                             dioxamate                10       Gm.                                         Dicalcium phosphate      1,000    Gm.                                         Methylcellulose, U.S.P. (15 cps)                                                                       60       Gm.                                         Talc                     150      Gm.                                         Corn starch              200      Gm.                                         Magnesium stearate       10       Gm.                                         ______________________________________                                    

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in preventing hay fever or asthma attacks at adose of one tablet every six hours.

EXAMPLE 3

One thousand tablets, each containing 4 mg. of DibenaylN,N'-(2,6-pyridinediyl)dioxamate are prepared from the following typesand amounts of ingredients:

    ______________________________________                                        Dibenzyl N,N'-(2,6-pyridinediyl)-                                             dioxamate                4        Gm.                                         Microcrystalline cellulose NF                                                                          410      Gm.                                         Starch                   100      Gm.                                         Magnesium stearate powder                                                                              3        Gm.                                         ______________________________________                                    

The ingredients are screened and blended together and pressed intotablets.

The tablets are useful to protect against food allergy at a dose of onetablet before meals.

EXAMPLE 4

A sterile preparation suitable for intramuscular injection andcontaining 0.1 mg. of Dibenzyl N,N'-(2,6-pyridinediyl)dioxamate in eachmilliliter is prepared from the following ingredients:

    ______________________________________                                        Dibenzyl N,N'-(2,6-pyridinediyl)-                                             dioxamate, micronized  0.1       Gm.                                          Benzyl benzoate        200       ml.                                          Methylparaben          1.5       Gm.                                          Propylparaben          0.5       Gm.                                          Cottonseed oil q.s.    1,000     ml.                                          ______________________________________                                    

One milliliter of this sterile preparation is injected for prophylactictreatment of allergic rhinitis.

EXAMPLE 5

Six hundred ml. of an aqueous dispersion containing 3.0 mg. of theDibenzyl N,N'-(2,6pyridinediyl)dioxamate per ml. is prepared as follows:

    ______________________________________                                        Dibenzyl N,N'-(2,6-pyridinediyl)-                                             dioxamate, micronized  1.8       Gm.                                          Sodium chloride        5         Gm.                                          Water for injection q.s.                                                                             600       ml.                                          ______________________________________                                    

The compound of the above formulation and sodium chloride are dispersedin sufficient water to make 600 ml. and sterilized.

The liquid is placed in nebulizers designed to deliver 0.25 ml. perspray.

The liquid is inhaled into the lungs every four to six hours forprevention of asthmatic attacks.

EXAMPLE 6

A powder mixture consisting of 0.2 gram of DibenzylN,N'-(2,6-pyridinediyl)dioxamate and sufficient lactose to make fivegrams of mixture is micropulverized and placed in an insufflatordesigned to deliver 50 mg. of powder per dose.

The powder is inhaled into the lungs every four to six hours forprevention of asthmatic attacks.

The powder is inhaled intranasally every four hours for prevention ofrhinitis.

EXAMPLE 7

A powder mixture consisting of 0.2 gram of diphenethylN,N'-(2,6-pyridinediyl)dioxamate and sufficient lactose to make fivegrams of mixture is micropulverized and placed in an insufflatordesigned to delivery 50 mg. of powder per dose.

The powder is inhaled into the lungs every four to six hours forprevention of asthmatic attacks.

The powder is inhaled intranasally every four hours for prevention ofrhinitis.

EXAMPLE 8

Twelve grams of an aerosol composition are prepared from the followingingredients:

    ______________________________________                                        Dibenzyl N,N'-(2,6-pyridinediyl)-                                             dioxamate, micronized  0.100 Gm.                                              Freon 12               1.440 Gm.                                              Freon 114              2,160 Gm.                                              Water                  7.700 Gm.                                              Sorbitan monoleate     0.600 Gm.                                              ______________________________________                                    

The compound is dispersed in the water and chilled to -30°C. and addedto the chilled Freons. The twelve grams of compositions are added to a13 ml. plastic coated bottle and capped with a metering valve. Themetering valve releases 80 mg. of composition in an aerosol. The aerosolis inhaled every four to six hours for prevention of asthmatic attacks.

EXAMPLE 9

After allowing for the differing solubilities of the compounds and theactivity of the particular compound as measured, for example, by the invivo rat passive cutaneous anaphylaxis assay, a suitable quantity ofeach of the compounds of Table II through Table IV and Example 1 issubstituted for the active compound in the compositions and uses ofExamples 2 through 8. Results showing anti-allergy activity areobtained.

It should be noted that in all the compositions and treatment examplesof this patent application, the quantity of drug employed refers to theacid equivalent.

The diesters of this patent application, preferably the dibenzyl anddiphenethyl compounds, can have longer durations of activity.

When repeated administration is desired, the compounds of thisapplication which have a relatively short duration of activity can beadministered in a priming dose-maintenance dose regimen as described inU.S. Ser. No. 403,677 at Page 21, line 28, to Page 22, line 16.

We claim:
 1. Compound of the formula ##SPC8##and N-oxides thereofwherein each ##EQU14## group is located anywhere on the carbon ring withthe proviso that one group cannot be ortho to the other group; X and Yare the same or different and are selected from the group consisting ofhydrogen, alkyl of 1 to 4 carbon atoms, inclusive, phenyl, alkoxy from 1to 4 carbon atoms, inclusive, nitro, amino, trifluoromethyl, halogen,and ##EQU15## wherein D is selected from the group consisting ofhydrogen, alkyl of 1 to 6 carbon atoms, inclusive, and a physiologicallyacceptable metal or amine cation; R₁ and R₂ are the same or differentand are selected from the group consisting of hydrogen; aphysiologically acceptable metal or amine cation; alkyl of 7 to 12carbon atoms, inclusive; cycloalkyl of 4 to 8 carbon atoms, inclusive;##SPC9## wherein p is an integer of 0 to 4, inclusive, and S is selectedfrom the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,inclusive, phenyl, halogen, trifluoromethyl, hydroxy, alkoxy of 1 to 4carbon atoms, inclusive, amino, nitro, carboxy, and ##EQU16## wherein R₃and R₄ are the same or different and are selected from the groupconsisting of hydrogen and alkyl of one to four carbon atoms, inclusive;with the proviso that when p is zero, S is not hydrogen; and ##EQU17##wherein b is an integer of 2 to 4, inclusive, and R₅ and R₆ are the sameor different and are selected from the group consisting of hydrogen andalkyl of one to four carbon atoms, inclusive, with the further provisothat when one of R₁ and R₂ is hydrogen or a physiologically acceptablemetal or amine cation, the other variable is not hydrogen or a metal oramine cation; and physiologically acceptable acid addition saltsthereof.
 2. Compound in accordance with claim 1 wherein X and Y are thesame or different and are selected from the group consisting ofhydrogen, alkyl of 1 to 4 carbon atoms, inclusive, phenyl, alkoxy of 1to 4 carbon atoms, inclusive, nitro, trifluoromethyl, and ##EQU18## 3.Compound in accordance with claim 2 wherein the ##EQU19## group is atthe 2 or 5 position and when at the 2 position, ##EQU20## is at the 6position and when the ##EQU21## group is at the 3 position, ##EQU22## isat the 5 position.
 4. Compound in accordance with claim 3 wherein X ishydrogen, Y is selected from the group consisting of hydrogen, alkyl ofone to four carbon atoms, inclusive, alkoxy of one to four carbon atoms,inclusive, nitro trifluoromethyl, halogen, and ##EQU23## R₁ and R₂ arethe same or different and are selected from the group consisting ofalkyl of 7 to 10 carbon atoms, inclusive, and ##SPC10##wherein p is aninteger of 0 to 4, inclusive, and S is selected from the groupconsisting of hydrogen, alkyl of 1 to 4 carbon atoms, inclusive, alkoxyof 1 to 4 carbon atoms, inclusive, halogen and carboxy, with the provisothat when p is zero, S is not hydrogen.
 5. Compound in accordance withclaim 4 wherein Y is at postion
 4. 6. Compound in accordance with claim5 wherein ##EQU24## is at position 2 and ##EQU25## is at position
 6. 7.Compound in accordance with claim 6 wherein when Y is halogen, halogenis selected from the group consisting of fluoro, chloro and bromo;R₁ andR₂ are the same or different and are selected from the group consistingof alkyl of 7 to 10 carbon atoms, inclusive, and ##SPC11## wherein p is1 or 2 and S is selected from the group consisting of hydrogen, alkyl of1 to 4 carbon atoms, inclusive, fluoro, chloro, bromo, and carboxy. 8.Compound in accordance with claim 4 with the proviso that N-oxides areexcluded and R₁ and R₂ are selected from the group consisting of alkylof 7 to 10 carbon atoms, inclusive, and ##SPC12##wherein p is 1 or 2 andS is selected from the group consisting of hydrogen, alkyl of 1 to 4carbon atoms, inclusive, fluoro, chloro, bromo, and carboxy.
 9. Compoundin accordance with claim 5 with the proviso that N-oxides are excludedand R₁ and R₂ are selected from the group consisting of alkyl of 7 to 10carbon atoms, inclusive, and ##SPC13##wherein p is 1 or 2 and S isselected from the group consisting of hydrogen, alkyl of 1 to 4 carbonatoms, inclusive, fluoro, chloro, bromo, and carboxy.
 10. Compound inaccordance with claim 6 with the proviso that N-oxides are excluded andR₁ and R₂ are selected from the group consisting of alkyl of 7 to 10carbon atoms, inclusive, and ##SPC14##wherein p is 1 or 2 and S isselected from the group consisting of hydrogen, alkyl of 1 to 4 carbonatoms, inclusive, fluoro, chloro, bromo, and carboxy.
 11. Compound inaccordance with claim 7 with the proviso that N-oxides are excluded. 12.Compound in accordance with claim 1 wherein R₁ is the same as R₂. 13.Compound in accordance with claim 4 wherein R₁ is the same as R₂. 14.Compound in accordance with claim 7 wherein R₁ is the same as R₂. 15.Dibenzyl N,N'(2,6-pyridinediyl)dioxamate.